Rotaviruses (RVs) are the single most important cause of severe diarrhea in infants and young children worldwide, causing approximately one-third to one-half of these illnesses. They infect almost all infants and young children in both developed and developing countries regardless of hygienic conditions, but the consequences of such infections are strikingly different: over 870,000 infants and young children die annually from RV diarrhea in the developing countries, whereas in this same age group in the United States (US) fewer than 100 die annually, but doctor visits reach about 500,00 and hospitalizations about 50,000 to 100,000. The need for a RV vaccine is compelling. We developed a RV vaccine that contains four components in order to protect against the four epidemiologically important RV serotypes. It is comprised of rhesus rotavirus (RRV) representing serotype 3 (the Jennerian approach), and three human RV-RRV reassortants, each possessing ten RRV genes and a single human RV gene that encodes VP7 (a major outer shell protein) that is responsible for serotype 1, 2, or 4 specificity (the modified Jennerian approach). Efficacy trials of this orally delivered vaccine have been completed in over 10,000 infants and young children with single or multiple vaccine components with successful results in most but not all studies. The quadrivalent formulation, given orally in three doses, has been shown to be effective in five trials: protective efficacy against severe RV diarrhea ranged from 69% among American Indians, to 80% or greater in two multicenter trials in the U.S., to 88% in Venezuela, to 91% in Finland. The vaccine was 75% to 100% effective in preventing dehydrating diarrheal illnesses. Particularly relevant was the 88% efficacy trial in Venezuela, because it was conducted in a poor socioeconomic area, indicating that the vaccine could protect in a developing country setting. Because of the demonstrated safety (transient fever) and efficacy of the quadrivalent vaccine, on January 31, 1997 Wyeth Laboratories, the licensee, submitted a Product License Application to the Food and Drug Administration (FDA). On December 12, 1997, The Vaccines and Related Biological Products Advisory Committee of the FDA Center for Biologics Evaluation and Research concluded that the clinical data presented to the Committee supported the safety and efficacy of the quadrivalent vaccine. Moreover, on February 11, 1998, and again on June 25, 1998, The Advisory Committee on Immunization Practices (ACIP) which "...provides advice and guidance to the Secretary, the Assistant Secretary for Health, and the Director, Centers for Disease Control and Prevention (CDC) on the most effective means to prevent vaccine preventable diseases..." recommended "...routine immunization for all infants with three oral doses of rotavirus vaccine at ages 2, 4, and 6 months." They further noted that "Because natural rotavirus infections occur early in life, RRV-TV should be incorporated into the routine childhood immunization schedule." Licensing of the vaccine by the FDA is anticipated in the not-too-distant future. We are also evaluating several second generation vaccines which may be non-reactogenic or would be available if the RRV-based vaccine fails to yield the optimal level of protection in epidemiological situations not yet tested. We had previously developed reassortant RVs that possess a single VP7 gene with serotype 1, 2, 3, or 4 specificity and the remaining ten genes from bovine RV (UK). Individual components have been evaluated in adults, children and infants and found to be safe and immunogenic. They were combined into a quadrivalent formulation and evaluated similarly and proved to be safe and immunogenic. This vaccine is currently in a field trial in which reactogenicity, immunogenicity and efficacy of two doses are under evaluation.